Thrombocytopenia is a disorder in which the number of platelets in the blood is abnormally low. Drug-induced immune thrombocytopenia is a condition where the use of certain drugs leads to the formation of antibodies against platelets. These antibodies can cause a decrease in platelet count, resulting in the potential for increased bleeding and decreased ability for clotting. If these antibodies are formed during pregnancy, they may pass from the mother to the fetus.
Heparin is the most widely used intravenous anticoagulant and one of the most widely prescribed drugs in the United States. More than 1 trillion units are administered annually to approximately 12 million patients. Intravenous heparin is commonly used for the prophylaxis and treatment of thromboembolic disease, as well as numerous other applications including certain types of lung and heart disorders, and during or after a variety of surgery including open heart, bypass, dialysis and orthopedic procedures. Heparin is also used for diagnostic and therapeutic interventional radiologic procedures. Due to the widespread use of unfractionated and low molecular weight heparins, heparin-induced thrombocytopenia (HIT) is considered to be the most frequent (and potentially the most devastating) drug-induced thrombocytopenia (Picker S. M. et al. Pathophysiology, epidemiology, diagnosis and treatment of heparin-induced thrombocytopenia (HIT). Eur J Med Res. 2004 Apr. 30; 9(4):180-5. Review).
HIT is classified into Type I and Type II, Type I being benign and Type II severe. Type I HIT occurs early after heparin initiation, the platelet levels are reduced only slightly and usually return to normal even when heparin treatment is continued. Thromboembolic complications are rare and Type I HIT is not antibody-mediated.
In contrast, Type II HIT is caused by antibody formation to heparin-platelet factor 4 complexes (Harenberg J. et al. Heparin-induced thrombocytopenia: pathophysiology and new treatment options. Pathophysiol Haemost Thromb. 2002 September-December; 32(5-6):289-94. Review). Type II HIT typically develops between 5 and 14 days after heparin therapy is started. The hallmark symptoms of Type II HIT are a drastic fall in platelet count and thrombosis, which can lead to limb gangrene (requiring leg amputation) or even death. Other symptoms of Type II HIT may include cutaneous reactions, from a simple allergic reaction to lesions to necrosis.
Type II HIT occurs in approximately 1-5% of patients treated with heparin (Goor Y. et al. Heparin-induced thrombocytopenia with thrombotic sequelae: a review. Autoimmun Rev. 2002 August; 1(4):183-9. Review). More alarmingly, 25-50% of post-cardiac surgery patients develop these heparin-dependent antibodies during the next 5 to 10 days (Warkentin T. E. et al. Heparin-induced thrombocytopenia and cardiac surgery. Ann Thorac Surg. 2003 December; 76(6):2121-31. Review). The rate of mortality and amputation in Type II HIT is estimated to be 30% and 20%, respectively (Picker S. M. et al. supra.).
Early diagnosis of HIT is essential to reduce morbidity and mortality. Currently, there are three methods of detecting heparin-induced antibodies: (1) functional tests such as the 14C-serotonin release assay (Sheridan D. et al. A diagnostic test for heparin-induced thrombocytopenia. Blood. 1986 January; 67(1): 27-30); (2) platelet aggregation tests (Chong B. H. et al. The clinical usefulness of the platelet aggregation test for the diagnosis of heparin-induced thrombocytopenia. Thromb Haemost. 1993 Apr. 1; 69(4): 344-50); and (3) immunoassays such as enzyme-linked immunosorbent assay (ELISA). Although serologic assays to detect and identify platelet-reactive antibodies have progressed from less sensitive and specific Phase I tests (e.g., those that measure platelet functional endpoints) through more sensitive Phase II assays (e.g., those that detect platelet-associated immunoglobulins), to highly specific Phase III assays (e.g., those that detect antibodies bound to alloantigens located on isolated platelet surface glycoproteins), these tests are used primarily as confirmation of HIT after the symptoms are seen in a patient and take many hours to perform. A more efficient, sensitive and specific assay to diagnose HIT remains elusive.